Ketamine, also known as (R,S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone, is a noncompetitive N-methyl-D-aspartate receptor antagonist that has been in use as a dissociative anesthetic for over fifty years. More recently, ketamine has been used in treating other conditions, for example, to alleviate pain, depression, symptoms associated with acute brain injury and stroke, epilepsy, alcohol dependence, Alzheimer's disease, asthma and other disorders. Non-competitive NMDA receptor antagonism may be associated with the analgesic effects; opiate receptor binding may contribute to analgesia and dysphoric reactions; and sympathomimetic properties may result from enhanced central and peripheral monoaminergic transmission. Ketamine appears to block dopamine uptake and therefore elevates synaptic dopamine levels. Ketamine is available as a racemic mixture. It has been commercially supplied as the hydrochloride salt in 0.5 mg/mL and 5 mg/mL ketamine base equivalents. For induction of 5-10 minutes of surgical anesthesia, a dose of 1.0-4.5 mg/kg may be intravenously administered; 6.5-13 mg/kg may be given intramuscularly for 12-25 minutes of surgical anesthesia.
Norketamine, or N-desmethylketamine, also known as (R,S)-2-(2-chlorophenyl)-2-(amino)cyclohexanone, is the major active metabolite of ketamine which is subject to the first-pass liver metabolism via N-demethylation. Like ketamine, norketamine acts as a noncompetitive NMDA receptor antagonist (Ki=1.7 μM and 13 μM for (S)-(+)-norketamine and (R)-(−)-norketamine, respectively), but is about 3-5 times less potent as an anesthetic in comparison. The elimination half-life of ketamine has been estimated at 2-3 hours, and 4 hours for norketamine.
Recently, it has been shown that frequent or chronic use of ketamine may cause impaired cognitive function. For example, people who chronically abuse ketamine have been shown to demonstrate impaired cognitive processing speed, verbal learning, and episodic, semantic, and working memory compared with healthy controls. See, e.g., Kim et al., Pain Medicine 2016; 17:1447-1451.
Dravet syndrome is a form of developmental encephalopathy associated with mutations of the SCN1A and SCN2A genes. According to the Dravet Syndrome Foundation, it is a rare, catastrophic, disease that begins in the first year of life with frequent and/or prolonged seizures. Dravet syndrome affects 1:15,700 individuals, 80% of whom have a mutation in their SCN1A gene. While seizures persist, other comorbidities such as developmental delay and abnormal EEGs are often not evident until the second or third year of life. Other than seizures, common issues associated with Dravet syndrome include behavioral and developmental delays, movement and balance issues, orthopedic conditions, delayed language and speech issues, growth and nutrition issues, sleeping difficulties, chronic infections, sensory integration disorders, and disruptions of the autonomic nervous system (e.g., regulation of body temperature and sweating). Current treatment options are limited, and the constant care required for someone suffering from Dravet syndrome can severely impact the patient's and the family's quality of life. Patients with Dravet syndrome face a 15-20% mortality rate.